MR monitoring of PTC124 treatment in DMD. This application addresses broad challenge area (03) Biomarkers Discovery and Validation and Specific Challenge Topic;03-AR 104: Imaging Biomarkers. DMD is one of the most devastating genetically linked neuromuscular diseases and is characterized by the absence of dystrophin, resulting in progressive muscle weakness, loss of walking ability and premature death. Despite the poor prognosis for patients with muscular dystrophy, therapeutic interventions have been lacking, and outcome measures for clinical trials have been limited to measures of muscle function and quality of life, serum biomarkers of muscle breakdown and invasive muscle biopsies. Additional noninvasive biomarkers that are sensitive to changes in muscle structure and composition are needed to facilitate the rapid translation of promising new interventions from preclinical studies to clinical trials. Therefore, the objective of this study is to validate the potential of magnetic resonance imaging (MRI) and spectroscopy (MRS) to monitor disease progression and the response to therapeutic interventions in children with DMD. The proposed study capitalizes on the recently initiated PTC124 phase 2a extension study, which involves the long-term administration (96 weeks) of PTC124, a novel stop codon suppression drug. Up to 15% of boys with DMD fail to make dystrophin because of a point mutation that creates a premature stop codon in the dystrophin mRNA. Stop codon suppression drugs, such as PTC124, allow the stop codon to be ignored and the entire dystrophin to be translated. Phase 1 and 2a testing have shown that orally bioavailable PTC124 is well tolerated, induces partial restoration of full-length dystrophin production and reduces muscle fragility in both mdx mice and boys with nonsense-mutation-mediated DMD. In the proposed study we will enroll 20 ambulatory boys participating in the phase 2a extension study to determine the ability of MRI/MRS to monitor the short and long term effect of PTC124 treatment on skeletal muscle. Magnetic resonance measurements of muscle damage/inflammation, muscle contractile tissue and intramuscular lipid accumulation will be performed in the lower extremity muscles prior to, and at multiple time points following initiation of PTC124 treatment. A subgroup of boys (n=20) not currently treated with PTC124 will be tested at the same time points and serve as controls. Ultimately, imaging data will be correlated with functional and histological outcome measures of disease progression/regression. This study provides an unprecedented opportunity to validate the potential of MRI/MRS to monitor the efficacy of therapeutic interventions targeting the restoration of dystrophin production in boys with DMD. We anticipate that the MR techniques developed and validated in this proposal will be suitable for clinical trials in a wide range of muscular dystrophies. The University of Florida and the University of Pennsylvania contribute substantially to the local and regional economy. In 2008, UF created 2,525 jobs and recent studies have shown that UF contributes nearly $6 billion annually to Florida's economy. The university employs about 34,000 people directly on its main campus and via UF organizations, such as the Institute of Food and Agricultural Sciences, is responsible for the creation of 74,894 jobs statewide. Penn Medicine created about 37,000 jobs and $5.4 billion in regional economic activity in 2008, with the area's highly trained workforce producing more than 24,600 applications for just 840 open Penn staff research positions. The current proposal will create or retain at least 14 jobs across two different states and all the infrastructure is in place to immediately initiate the project. Public Health Relevance: The goal of this project is to develop a way to observe whether or not new therapies are effective in correcting the disease process in muscles of boys with Duchenne muscular dystrophy (DMD) without the need to take muscle biopsies. To date, the only relatively noninvasive method of monitoring the disease process is unreliable and measures blood levels of creatine kinase. We have evidence in mouse models of both DMD and limb girdle muscular dystrophy, that magnetic resonance imaging can be used to track disease progression and monitor the efficacy of therapeutic interventions. We will extend our past mouse studies to boys who are participating in the Phase 2a clinical trial of PTC124, a promising new drug for DMD boys with premature stop codons. The availability of a reliable, nondestructive monitoring method that can be routinely and repeatedly implemented in patients will greatly benefit clinical trials in muscle diseases.